Page 98 - Genomic Medicine in Emerging Economies

Familial Adenomatous Polyposis 87

FAP is caused by mutations in the tumor suppressor gene APC (adenomatous
polyposis coli gene), located in chromosome 5q21-22 (Leppert et al., 1987;
Nakamura et al., 1988; Kinzler et al., 1991). The APC gene consists of 15 cod-
ing exons, and its cDNA spans more than 8529 bp (Groden et al., 1991). It
encodes a protein whose main function is partially controlling the cell-cycle
progression by participating in the Wnt signaling pathway. The APC protein
regulates the degradation of β-catenin, a transcriptional activator of genes,
such as cyclin D1 and c-myc proto-oncogenes (He et al., 1998).
To date more than 1700 different APC genetic alterations have been reported
in The Human Gene Mutation Database (HGMD; http://www.hgmd.cf.ac.uk/)
and more than 1190 genetic alterations have been described in the Leiden Open
Variation Database (LOVD; http://www.lovd.nl/APC). Most of them correspond
to nonsense (24%) and frameshift (59%) type, resulting in truncated proteins.
Different studies in patients with FAP have shown a high correlation between
the site of the mutation and the clinical phenotype, such as grade of sever-
ity and/or the presence of extracolonic manifestations (Fearnhead et al., 2001;
Merg et al., 2005; Galiatsatos and Foulkes, 2006). Mutations located between
codons 1255 and 1467 are associated with the presence of more than 1000
polyps in the colon and rectum (Nagase et al., 1992). However, mutations in
the 5′ and 3′ ends of the gene have been associated with attenuated FAP with
less than 100 polyps (Spirio et al., 1993; Friedl et al., 1996). Conversely, diverse
extracolonic features, such as osteomas, congenital hypertrophy of retinal pig-
ment epithelium (CHRPE), and desmoid tumors, correlate with mutations in a
specific region of the APC gene between codons 767 and 1513, 457 and 1444,
and 1310 and 2011, respectively (Caspari et al., 1995; Bertario et al., 2003;
Bisgaard and Bülow, 2006). Among all mutations described, the most frequent
are c.3183_3187delACAAA and c.3927_3931delAAAGA, also called hot spots
1061 and 1309, respectively. Patients carrying the latter mutation have been
found in different populations and present a profuse polyposis and early-onset
age of the disease (Caspari et al., 1994).

Mutational Screening of APC Gene in Latin America
To date five Latin American countries have reported studies on the mutational
screening of the APC gene in FAP patients: Argentina, Brazil, Chile, Cuba
Puerto Rico (Cruz-Bustillo et al., 2002; De Rosa et al., 2004; De La Fuente et al.,
2007; Cruz-Correa et al., 2013; De Queiroz Rossanese et al., 2013; Torrezan
et al., 2013). One additional report showed the findings for nine Hispanic
patients from México, Guatemala, and Honduras (Ricker et al., 2010b). As
shown in Table 5.5, a total of 163 patients have been studied, whose main cri-
terion of selection was classic FAP (n = 116) and a lower proportion of patients
with attenuated phenotype (n = 10) and with an unknown number of polyps
(n = 37). The percentage of patients with mutations varies significantly among